Alzheimer's Disease (AD)
The prevalence and incidence of Alzheimer's disease, and its devastating effects on the lives of patients and caregiver families are well known. The health care costs to society are onerous, and continues to grow with the aging population. Enormous strides have been made in understanding the pathology of the disease which leads to the build-up of amyloid plaques in the brain, which plaques are aggregates of amyloid beta (Aβ) peptides. Fundamental advances have been made in discovering inhibitors of the extra-cellular and intra-cellular neuronal biochemical enzymes such as β-secretase (BACE1) or γ-secretase (GS) to stop the amyloid or intraneuronal τ-tangles build-up; and even reverse these processes through treatment with specific monoclonal antibodies. However, in spite of massive scientific research and investments in reversing the cognitive decline of AD, these have yielded scant benefits. Consensus is emerging that the best approach would be to treat patients before the disease has progressed too far, and even before disease symptoms become apparent. Multi-targeted Alzheimer's drugs, for example dual BACE/acetylcholine esterase inhibition or GSM/PPARγ active agents would offer additional benefits (Harrie J. M. Gisjen, et al., “Secretase Inhibitors and Modulators as a Disease-Modifying Approach Against Alzheimer's Disease”, Annual Reports in Medicinal Chemistry, 2012, 47, 55-69). Gamma secretase modulators (GSMs) cause a product shift from the longer amyloid forming Aβ peptide isoforms such as Aβ42 and Aβ40 to shorter more soluble Aβ39-Aβ37 isoforms which more easily clear from the brain than aggregate into plaques.
NSAIDS
Non-steroidal anti-inflammatory drugs, commonly known as NSAIDS are a class of drugs in ubiquitous clinical use as pain relievers or analgesics for over 60 years. The most used agents in this category are ibuprofen and naproxyn, and includes aspirin. These are usually characterized by an alkyl or alkoxyl substituted aromatic ring attached to an aliphatic —CH—(CH3)—COOH moiety. In early 2000's the NSAID compound tarenflurbil (R-isomer), was clinically tested in mild AD patients. It failed large scale clinical trials, which failure was attributed to its low potency at inhibiting formation of toxic Aβ42 peptide and its weak ability at crossing the blood brain barrier. Since then numerous other NSAID GSMs, such as CHF-5074 and JNJ-40418677 having potent Aβ42 IC50 and greater brain penetration, have entered clinical trials to treat mild symptoms of AD (Harrie J. M. Gisjen, et al., “Secretase Inhibitors and Modulators as a Disease-Modifying Approach Against Alzheimer's Disease”, Annual Reports in Medicinal Chemistry, 2012, 47, 55-69; Todd E. Goldie et al., “γ-Secretase inhibitors and modulators”, Biochimica et Biophysica Acta (BBA)—Biomembranes, Volume 1828; Vol. 12, December 2013, 2898-2907).
The presence of omega-3 fatty acids, especially DHA in the brain is ubiquitous. Clinical studies in 4 year old children support the beneficial effects of docohexaenoic acid (DHA) on cognitive function (NCT 00351624; 2006-2008; sponsored by Martek BioSciences Corporation). It would be an interesting study to follow such treated children over decades regarding the incidence of onset of symptoms of Alzheimer's disease relative to the untreated group. In the meantime, it is worth exploring in a prospective study, if a DHA NSAID either alone, or in combination with another gamma secretase modulator (GSM) or other prescribed clinical agents, would slow down the decline of cognitive function in early stage AD patients.
PUFAs
Omega-3 oils or omega-3 fatty acids are naturally occurring, straight-chain (16-24 carbons) fatty carboxylic acids (PUFAs), essential for normal metabolism in humans and other animals. Since the omega-3 fatty acids are not synthesized by the human body, they are recommended to be taken as dietary supplements in 1-4 grams daily for cardiovascular health benefits, preventing strokes, and reducing blood pressure. (Delgado-Lista, J., et al., “Long Chain Omega-3 Fatty Acids and Cardiovascular Disease: A Systematic Review.” The British Journal of Nutrition, June 2012, 107 Suppl 2, S201-13).
Omega-3 fatty acids have 3-6 conjugated carbon-carbon double bonds and are so named as the first carbon with unsaturation is 3rd carbon from the distal carboxylic acid carbon. All double bonds are in the cis configuration. Among the omega-3 fatty acids are eicosapentanenoic acid (EPA, 20 carbons, 5 conjugated double bonds), docohexaenoic acid (DHA, 22 carbons, 6 conjugated double bonds) and α-linolenic acid (ALA, 18 carbons, 3 conjugated double bonds), these are the most studied PUFAs pharmacologically.
Clearly, improvement in the treatment of AD is still sought.